2026/01/08 by Christopher J. Lupton, Charles Bayly-Jones, Shuqi Dong +12 · 2 voices · 6 citations
Biochemistry, Genetics and Molecular Biology · #Adenosine triphosphate #Amino acid #Cellular transport and secretion #Docking (animal) #GTP' #GTPase #Guanosine #Guanosine triphosphate #Lysosome #Microtubule and mitosis dynamics #PI3K/AKT/mTOR signaling in cancer #Triphosphatase #mTORC1
paper · doi:10.1016/j.cell.2025.12.005
published in Cell 189(4), 1185-1200.e28 (Cell Press)
openalex publication_date 2026/01/08 · openalex created_date 2026/01/09 · openalex updated_date 2026/07/22
The guanosine triphosphate (GTP)-bound state of the heterodimeric Rag GTPases functions as a molecular switch regulating mechanistic target of rapamycin complex 1 (mTORC1) activation at the lysosome downstream of amino acid fluctuations. Under low amino acid conditions, GTPase-activating protein (GAP) activity toward Rags 1 (GATOR1) promotes RagA GTP hydrolysis, preventing mTORC1 activation. KICSTOR recruits and regulates GATOR1 at the lysosome by undefined mechanisms. Here, we resolve the KICSTOR-GATOR1 structure, revealing a striking ∼60-nm crescent-shaped assembly. GATOR1 anchors to KICSTOR via an extensive interface, and mutations that disrupt this interaction impair mTORC1 regulation. The S-adenosylmethionine sensor SAMTOR binds KICSTOR in a manner incompatible with metabolite binding, providing structural insight into methionine sensing via SAMTOR-KICSTOR association. We discover that KICSTOR and GATOR1 form a dimeric supercomplex. This assembly restricts GATOR1 to an orientation that favors the low-affinity active GAP mode of Rag GTPase engagement while sterically restricting access to the high-affinity inhibitory mode, consistent with a model of an active lysosomal GATOR1 docking complex.